Digenic inheritance of variants in RYR1 and PLEC causing myopathy with tubular aggregates

Article Sidebar

PDF
Published Jun 29, 2025
DOI: https://doi.org/10.18103/mra.v13i6.6564

Downloads

Download data is not yet available.

Submit your own article

Register as an author to reserve your spot in the next issue of the Medical Research Archives.

Author Registration

Join the Society

The European Society of Medicine is more than a professional association. We are a community. Our members work in countries across the globe, yet are united by a common goal: to promote health and health equity, around the world.

Join Europe’s leading medical society and discover the many advantages of membership, including free article publication.

Membership

Main Article Content

Leema Reddy Peddareddygari
Dynamic Biologics Inc., 1 Deer Park drive, Monmouth Junction, New Jersey, USA, 08852
Arman Singh Grewal
Larner College of Medicine, University of Vermont, Vermont, USA, 05401
Raji P. Grewal
Dynamic Biologics Inc., 1 Deer Park drive, Monmouth Junction, New Jersey, USA, 08852; Capital Institutes for Neurosciences, 100K. Johnson Blvd North, Suite 201, Bordentown, New Jersey, USA, 08505

Abstract

Despite the advances in genetic testing, a significant proportion of patients with suspected genetic myopathies remain undiagnosed. In these patients, the standard patterns of transmission of single gene disorders which include autosomal dominant, autosomal recessive or X-linked are investigated. However, an under recognized phenomenon that could be considered is digenic inheritance in which variants in two separate genes established to cause myopathy result in the phenotype. We report a 53-year-old man who had complaints of fatigability and weakness. Following neurological examination and electrophysiological testing he was diagnosed with a myopathy. Muscle biopsy confirmed the presence of a myopathy with tubular aggregates without inflammatory features, and a genetic etiology was suspected. There was no family history to suggest an autosomal dominant pattern of inheritance and no family members available for further study. Whole exome sequencing was performed and revealed variants in multiple genes including the ryanodine receptor 1 (RYR1) gene, Kelch repeat and BTB (POZ) domain containing 13, (KBTBD13) gene, spectrum repeat containing nuclear envelope protein 1 (SYNE1) gene and plectin (PLEC) gene. These variants were further analyzed for available published research papers and databases reporting pathogenicity, and frequency. In addition, we performed modeling for possible pathogenicity and protein/protein interactions for each of the variants. We hypothesize that in this patient, the ryanodine receptor 1 (RYR1) gene variant, c.1598 G>A, and plectin (PLEC) gene variant, c.2144 C>T following digenic inheritance are the cause of his genetic myopathy. Our study demonstrates that genetic diagnosis can be facilitated by recognition of digenic inheritance in patients with undiagnosed myopathies and the utility of the tools to analyze variants even if family members are not available for study.

Keywords: Digenic inheritance, myopathy, tubular aggregates, RYR1 gene and PLEC gene

Article Details

How to Cite
PEDDAREDDYGARI, Leema Reddy; GREWAL, Arman Singh; GREWAL, Raji P.. Digenic inheritance of variants in RYR1 and PLEC causing myopathy with tubular aggregates. Medical Research Archives, [S.l.], v. 13, n. 6, june 2025. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/6564>. Date accessed: 17 july 2025. doi: https://doi.org/10.18103/mra.v13i6.6564.
ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian
Issue
Vol 13 No 6 (2025): Vol.13, Issue 6, June 2025
Section
Research Articles

The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.

 

References

1. Nallamilli BRR, Chakravorty S, Kesari A, et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018;5(12):1574-1587. doi: 10.1 002/acn3.649.

2. Chakravorty S, Nallamilli BRR, Khadilkar SV, et al. Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. Front Neurol. 2020; 11:559327. doi: 10.3389/fneur.2020.5 59327.

3. Töpf A, Johnson K, Bates A, et al. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. Genet Med. 2020;22(9):1478-1488. doi: 10.1038/s41436-020-0840-3.

4. Peddareddygari LR, Grewal RP. Digenic inheritance in patients with undiagnosed myopathies. Medical Research Archives, 12(11) 2024. doi:10.1810 3/mra.v12i11.6046.

5. Posey JE, Harel T, Liu P, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017;376(1):21-31. doi: 10.1056/NEJMoa1516767.

6. Schäffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50(10):641-52.
doi: 10.1136/jmedgenet-2013-101713.

7. Neuhofer CM, Prokisch H. Digenic Inheritance in Rare Disorders and Mitochondrial Disease-Crossing the Frontier to a More Comprehensive Understanding of Etiology. Int J Mol Sci. 2024;25 (9):4602. doi: 10.3390/ijms25094602.

8. Deltas C. Digenic inheritance and genetic modifiers. Clin Genet. 2018;93(3):429-438. doi: 10.1111/cge.13150.

9. Kerner G, Bouaziz M, Cobat A, et al. A genome-wide case-only test for the detection of digenic inheritance in human exomes. Proc Natl Acad Sci U S A. 2020;117(32):19367-19375. doi: 10.1073/pna s.1920650117.

10. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001;11(5): 863-74. doi: 10.1101/gr.176601.

11. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-9. doi: 10.1038/nmeth0410-248.

12. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11(4): 361-2. doi: 10.1038/nmeth.2890.

13. Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1): D638-D646. doi: 10.1093/nar/gk ac1000.

14. Ibarra M CA, Wu S, Murayama K, et al. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006;104(6):1146-54. doi: 10.1097/00000542-200 606000-00008.

15. Miller DM, Daly C, Aboelsaod EM, et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018;121(4):944-952. doi: 10.1016/j.bja.2018.06.028.

16. Tammaro A, Bracco A, Cozzolino S, et al. Scanning for mutations of the ryanodine receptor (RYR1) gene by denaturing HPLC: detection of three novel malignant hyperthermia alleles. Clin Chem. 2003;49(5):761-8. doi: 10.1373/49.5.761.

17. Sato K, Roesl C, Pollock N, Stowell KM. Skeletal muscle ryanodine receptor mutations associated with malignant hyperthermia showed enhanced intensity and sensitivity to triggering drugs when expressed in human embryonic kidney cells. Anesthesiology. 2013;119(1):111-8. doi: 10.1097/A LN.0b013e31828cebfe.

18. Zhang J, Felder A, Liu Y, et al. Nesprin 1 is critical for nuclear positioning and anchorage. Hum Mol Genet. 2010;19(2):329-41. doi: 10.1093/hm g/ddp499.

19. Zrelski MM, Kustermann M, Winter L. Muscle-Related Plectinopathies. Cells. 2021;10(9):2480. doi: 10.3390/cells10092480.

20. Fan Q, Gwathmey K, Du X, Seth A, Corse A. Tubular aggregate myopathy causing progressive fatiguable weakness. Pract Neurol. 2024;24(2):137-140. doi: 10.1136/pn-2023-003838.

21. Vita G, Monici MC, Owaribe K, Messina C. Expression of plectin in muscle fibers with cytoarchitectural abnormalities. Neuromuscul Disord. 2003;13(6):485-92. doi: 10.1016/s0960-8966(03)00 037-3.

22. Okazaki A, Ott J. Machine learning approaches to explore digenic inheritance. Trends Genet. 2022; 38(10):1013-1018. doi: 10.1016/j.tig.2022.04.009.